Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to novel chemical entities that have biological activity to modulate mammalian protein kinase enzymes.
• Protein kinases are regulators of cellular signaling and their functional dysregulation common in carcinogenesis and many other disease states or conditions (Mizuguchi, Y. et al., Breast Tumor Kinase/Protein Tyrosine Kinase 6 (Brk/PTK6). J Hepatology 2015, 63, 399-407; Mahmoud, K. A. et al., Discovery of 4-Anilino ⁇ -Carbolines as Novel Brk Inhibitors. Bioorganic & Medicinal Chemistry Letters 2014, 24:1948-1951: Nobel, M. E. M. Protein Kinase Inhibitors: Insights into Drug Design from Structure. Science 2004, 303:1800-1805).
• Protein kinases regulate key signal transduction cascades that control or are involved in the control of physiological functions including cellular growth and proliferation, cell differentiation, cellular development, cell division, stress response, transcription regulation, aberrant mitogenesis, angiogeneisis, abnormal endothelial cell-cell or cell-matrix interactions during vascular development, inflammation, Jun-N-terminal kinase (JNK) signal transduction, and several other cellular processes (see U.S. Pat. No. 8,470,818). Protein kinase inhibitors have been established as promising drugs that inhibit overactive protein kinases in cancer cells (Mahmoud id.).
• a partial, non-limiting list of these kinases includes: BRK, FGR, PDGFR ⁇ (V561D), DDR2, LYNa, SRM, PDGFR ⁇ , LCK, DDR1, KDR, ACK, JAK1, LYNb, KIT, CSK, YES, KIT(V560G), BLK, MST1, JAK2, RET(S891A), SRC, FYN(isoform a), RET(G691S), FYN(isoform b), PDGFR ⁇ , RET, FLT4, RET(Y791F), skMLCK, FRK, MST2, FLT1, AurA, FLT3, JAK3, RET(M918T), WNK3, p388, FGFR2, MNK1, MNK2, PIK3CA/PIK3R1, PDGFR ⁇ (D842V), MET, FGFR1, BRAF(V600E), MAP2K5, KIT(D816E), ALK,
• novel compounds of this invention inhibit the activity of one or more protein kinases and are, therefore, expected to be useful in the treatment of kinase-related diseases or conditions.
• the present invention concerns compounds active on protein kinases in general.
• the present invention provides a compound having formula I:
• R 1 is a substituted lower alkyl or lower alkenyl, wherein the lower alkyl or lower alkenyl is substituted with one or more substituents selected from —OH, ⁇ O, and alkoxy; and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, and —NO 2 .
• the present invention provides a compound having formula II:
• R 1 is a substituted lower alkyl or lower alkenyl, wherein the lower alkyl or lower alkenyl is substituted with one or more substituents selected from —OH, ⁇ O, and alkoxy; and R 4 , R 5 , and R 8 are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, and —NO 2 .
• the present invention provides a compound having formula III:
• R 1 is a substituted lower alkyl or lower alkenyl, wherein the lower alkyl or lower alkenyl is substituted, with one or more substituents selected from —OH, ⁇ O, and alkoxy; and R 4 , R 5 , and R 10 are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, and —NO 2 .
• the present invention provides a compound having formula IV:
• R 1 is a substituted lower alkyl or lower alkenyl, wherein the lower alkyl or lower alkenyl is substituted with one or more substituents elected from —OH, ⁇ O, and alkoxy.
• the present invention provides compound having the structure of 200-17:
• the present invention provides a compound having the structure of 200-73:
• the present invention provides a compound having the structure of formula 200-93:
• the present invention provides a compound having the structure of formula 200-115:
• the present invention provides a compound having the structure of 200-117:
• the present invention provides a compound having the structure of 200-123:
• the present invention provides a compound having the structure of 200-139:
• the present invention provides a compound having the structure of 200-149:
• the invention provides a method for treating a protein kinase-mediated disease or condition in an animal or human subject wherein the method involves administering to the subject an effective amount of formulas I, II, III, or IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-123, 200-139 or 200-149.
• the terms “treat,” “therapy,” and like terms refer to the administration of compounds in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease condition, i.e., indication, and/or to prolong the survival of the subject being treated.
• protein kinase-mediated disease or condition refers to a disease or condition in which the biological function of a protein kinase affects the development, course, and/or symptoms of the disease or condition.
• a protein kinase-mediated disease or condition includes a disease or condition for which modulation provides a positive effect, i.e., one in which treatment with protein kinase inhibitors, including compounds described herein, provides a therapeutic benefit to the subject with or at risk of the disease or condition.
• the invention provides a method for treating a breast tumor related kinase (BRK) mediated disease or condition in a mammal, wherein the method involves administering to the subject an effective amount of a compound of the invention.
• BRK is also known as protein tyrosine kinase 6 (PTK6).
• PTK6 protein tyrosine kinase 6
• the term BRK mediated disease or condition refers to a disease or condition in which the biological function of BRK, including any mutations thereof, affects the development, course, and/or progression of the disease or condition, and/or in which modulation of BRK alters the development, course, and/or symptoms of the disease or condition.
• BRK includes, but is not limited to, BRK and mutations of BRK.
• the compounds of formula I, II, III, or IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-123, 200-139 or 200-149 described herein may be administered in an effective amount.
• An “effective amount” or “therapeutically effective amount” is an amount of a preparation that alone, or together with further doses, produces the desired response. Desired response may involve: (1) halting the progression of the disease or condition, (2) delaying the onset of the disease or condition, and (3) preventing the disease or condition from occurring, although it may also imply only slowing of the disease or condition.
• specification of a compound or group of compounds includes pharmaceutically acceptable salts, prodrugs(s), and all isomers (cis/trans; enantiomers, and diasteriomers) of such compounds.
• the invention provides for pharmaceutical compositions that include a therapeutically effective amount of a compound of formulas I, II, II, or IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-123, 200-139 or 200-149 in free form or in a pharmaceutically acceptable salt form and at least one pharmaceutically acceptable carrier, excipient, and/or diluent.
• chemical structure or “chemical substructure” is meant any definable atom or group of atoms that constitute an individually identifiable portion of a molecule, such as a substituent moiety, a core which is optionally substituted, and the like.
• chemical substructures of a ligand can have a role in binding of the ligand to a target molecule, or can influence, the three-dimensional shape, electrostatic charge, and/or conformational properties of the ligand.
• prodrug is a compound that, upon in vivo administration, is metabolized by one or more steps or processes or otherwise converted to the biologically, pharmaceutically, or therapeutically active form of the compound.
• the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes.
• binding in connection with the interaction between a target and a potential binding compound indicates that the potential binding compound associates with the target to a statistically significant degree as compared to association with proteins generally (i.e., non-specific binding).
• the term “modulating” or “modulate” refer to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as a protein kinase.
• a biological activity associated with a particular biomolecule
• an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e.g., an enzyme, by either increasing (e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor) its activity.
• This type of activity is typically indicated in terms of an inhibitory concentration (IC 50 ) for an inhibitor or an excitation concentration (EC 50 ) for an activator.
• the term “synthesizing” and like terms means chemical synthesis from one or more precursor materials. Further, by “assaying” is meant the creation of experimental conditions and the gathering of data regarding a particular result of the experimental conditions. For example, enzymes can be assayed based on their ability to act upon a detectable substrate. A compound or ligand can be assayed based on its ability to bind to a particular target molecule or molecules.
• lower alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups and branched-chain alkyl groups.
• a straight-chain or branched-chain alkyl has about 6 or fewer carbon atoms in its backbone (e.g., C1-C6 for straight chain, C3-C6 for branched chain).
• lower alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group 2 to 6 carbon atoms, referred to herein as C2-C6 alkenyl.
• cycloakyl refers to a 3 to 7 membered monocyclic ring of aliphatic groups, including C3-C7, that is optionally substituted with alkyl, alkenyl, alkoxyl, or optionally substituted amino, halogens, cyano (—CN), or nitro (—NO 2 ).
• aryl alone or in combination refers to a monocyclic or bicyclic ring system containing aromatic hydrocarbons such as phenyl or naphthyl, which may be optionally fused with a cycloalkyl of preferably 5 to 7 carbon atoms, more preferably 5 to 6 carbon atoms.
• heterocycloalkyl refers to a saturated or unsaturated 5 non-aromatic cycloalkyl group having from 5 to 10 carbon atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S, or N, and are optionally fused with benzo or heteroaryl of 5 to 6 ring members.
• alkoxyl or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
• Representative alkoxyl groups include methoxy, ethoxy, propyloxy tert-butoxy, and the like.
• substituted amines moiety that may be represented as NR 2 where R is independently hydrogen or alkyl.
• Halogen refers to chloro (Cl), fluoro (F), bromo (Br), or iodo (I).
• the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures.
• pharmaceutically acceptable means that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or condition to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for an injectable.
• salts refers to salts that are non-toxic in the amounts and concentrations at which they are administered.
• the preparation of such salts can facilitate pharmacological use by altering the physical characteristics of a compound (solubility) without preventing it from exerting its physiological effect.
• composition refers to a pharmaceutically active compound and one or more pharmaceutically acceptable carriers, excipients, and/or diluents.
• terapéuticaally effective amount or “effective amount” is an amount of a preparation that alone, or together with further doses, produces the desired response. This may involve halting the progression of the disease or condition, delaying the onset of the disease or condition, or preventing the disease or condition from occurring, although it may also imply only temporarily slowing of the disease or condition.
• protein kinase-mediated disease or condition refers to a disease or condition in which the biological function of a protein kinase affects the development, course, and/or symptoms of the disease or condition.
• mutants refers to single or multiple amino acid changes in a protein as compared to the wild-type protein amino acid sequence.
• the present invention provides a compound having formula I:
• R 1 is a substituted lower alkyl or lower alkenyl, wherein the lower alkyl or lower alkenyl is substituted with one or more substituents selected from —OH, ⁇ O, and alkoxy; and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, and —NO 2 .
• the present invention provides a compound having formula II:
• R 1 is a substituted lower alkyl or lower alkenyl, wherein the lower alkyl or lower alkenyl is substituted with one or more substituents selected from —OH, ⁇ O, and alkoxy; and R 4 , R 5 , and R 8 are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, and —NO 2 .
• the present invention provides a compound having formula III:
• R 1 is a substituted lower alkyl or lower alkenyl, wherein the lower alkyl or lower alkenyl is substituted with one or more substituents selected from —OH, ⁇ O, and alkoxy; and R 4 , R 5 , and R 10 are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, and —NO 2 .
• the present invention provides a compound having formula IV:
• R 1 is a substituted lower alkyl or lower alkenyl, wherein the lower alkyl or lower alkenyl is substituted with one or more substituents selected from —OH, ⁇ O, and alkoxy.
• the present invention provides a compound having the structure of 200-17:
• the present invention provides a compound having the structure of 200-73:
• the present invention provides a compound having the structure of 200-93 and the resolved isomers 200-93a and 200-93b:
• the present invention provides compound having the structure of 200-115:
• the present invention provides a compound having the structure of 200-117:
• the present invention provides a compound having the structure of 200-123:
• the present invention provides a compound having the structure of 200-139:
• the present invention provides a compound having the structure of 200-149:
• Protein kinases play key roles in propagating biochemical signals in diverse biological pathways. More than 500 kinases have been described, and specific kinases have been implicated in a wide range of diseases conditions.
• the invention provides methods for treating a protein kinase-mediated disease or condition in an animal or human subject, (i.e., indications) such as without limitation, cancer, cardiovascular disease, inflammatory disease, neurological disease, and other diseases. As such, kinases represent important control points for small molecule therapeutic intervention.
• the invention provides a method for modulating the activity of a protein kinase selected from the group consisting of BRK, FGR, PDGFR ⁇ (V561D), DDR2, LYNa, SRM, PDGFR ⁇ , LCK, DDR1, KDR, ACK, JAK1, LYNb, KIT, CSK, YES, KIT(V560G), BLK, MST1, JAK2, RET(S891A), SRC, FYN(isoform a), RET(G691S), FYN(isoform b), PDGFR ⁇ , RET, FLT4, RET(Y791F), skMLCK, FRK, MST2, FLT1, AurA, FLT3, JAK3, RET(M918T), WNK3, p38 ⁇ , FGFR2, MNK1, MNK2, PIK3CA/PIK3R1, PDGFR ⁇ (D842V), MET, FGFR1, BRAF(V600E),
• the invention provides a method for treating a protein kinase-mediated disease or condition in an animal subject, wherein the method involves administering to the subject an effective amount of a composition including a compound of formulas I, II, III, IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-123, 200-139 or 200-149.
• the invention provides a method for treating a disease or condition, mediated by a protein kinase selected from the group consisting of BRK, FGR, PDGFR ⁇ (V561D), DDR2, LYNa, SRM, PDGFR ⁇ , LCK, DDR1, KDR, ACK, JAK1, LYNb, KIT, CSK, YES, KIT(V560G), BLK, MST1, JAK2, RET(5891A), SRC, FYN(isoform a), RET(G691S), FYN(isoform b), PDGFR ⁇ , RET, FLT4, RET(Y791F), skMLCK, FRK, MST2, FLT1, AurA, FLT3, JAK3, RET(M918T), WNK3, p38 ⁇ , FGFR2, MNK1, MNK2, PIK3CA/PIK3R1 PDGFR ⁇ (D842V), MET, FGFR1, BRAF(V
• a number of different assays for kinase activity can be utilized for assaying for active modulators and/or determining specificity of a modulator for a particular kinase or group of kinases.
• assays for kinase activity can be utilized for assaying for active modulators and/or determining specificity of a modulator for a particular kinase or group of kinases.
• one of ordinary skill in the art will know of other assays that can be utilized or can be modified for a particular application.
• compounds 200-17, 200-73, 200-93a, 200-93b, 200-115, 200-117, 200-123, and 200-139 displayed low nM activity to greater than 30% inhibition of Breast tumor related kinase (BRK), or protein tyrosine kinase 6 (PTK6) BRK.
• BRK Breast tumor related kinase
• PTK6 protein tyrosine kinase 6
• inhibition of BRK is an important target for a cancer therapy, particularly breast cancer, as BRK participates in both cell dysregulation and metastasis.
• BRK inhibition may offer a therapeutic approach for treating patients with Her2 targeted therapy-resistant breast cancers and patients with ERBB2/HER2-positive breast cancers (see below).
• Protein kinase targets for compounds of formula I, II, III, and IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-123, 200-139 and 200-149 include the following: ALK, B-Raf, C-Raf-1, EGFR, Erk2, FGFR, Frk, Fyn, HCK, Her2/Erbb2, Her4/Erbb4, Jak1, Jak2, Jak 3, Kdr, Kit, LCK, MAP2K1, MAP2K2, MAPKAPK2, PDGFR, PDGFR ⁇ , PDGFR ⁇ , Ret, Src, TNF-Related Activation-Induced Cytokine (TRANCE), Stk6, Aurora A, Aurora B, Aurora C, and Yes (See U.S. Pat. No. 8,470,818 B2 for detailed information about the above listed kinases).
• BRK Breast tumor related kinase
• PTK6 protein tyrosine kinase 6
• BRK is a non-receptor type tyrosine kinase, cloned from a metastatic breast tumor, and overexpressed in a majority of breast cancers.
• BRK is expressed in many human cancers including breast, ovary, colon head and neck squamous cell carcinoma, prostate, lung, bladder, pancreas, and gastric, and lymphomas (Mizuguchi id.). BRK is only weakly expressed in normal mammary tissue or benign lesions (Mizuguchi id.).
• BRK has been shown to be activated downstream of various receptors in response to stimulation by their respective ligands such as EGF, HGF, and IGF (Goel, R. K. et al. Tracing the Footprints of the Breast Cancer Oncogene BRK—Past Till Present, Biochemica et Biophysics Acta 2015, 1656:39-54). Since the signaling pathways activated by these ligands tend to promote cell proliferation and migration, activation of BRK downstream in these signaling pathways is predicated to mechanistically contribute to the promotion of oncogenesis (Goal id.).
• BRK BRK6
• STAT3 signal transducer and activator of transcription 3
• BRK focal adhesion kinase
• BCAR1 breast cancer anti-estrogen resistance 1
• BRK is highly expressed in Human Epidermal Growth Factor 2+ (Her2+) breast cancers (Park id.). Park and co-workers investigated whether BRK inhibition is an effective strategy to inhibit growth and survival of Her2+ breast cancer cells, including those that are relatively resistant to Lapatinib, a targeted therapy for Her2+ breast cancer that developed either intrinsically or was acquired after continuous drug exposure. The authors reported that BRK down-regulation induces apoptosis of Lapatinib-resistant Her2(+) breast cancer cells by enhancing Bim, a pro-apoptotic Bcl2 family member expressed via p38 activation. As Bim expression is a critical biomarker for response to many targeted therapies, BRK inhibition may offer a therapeutic approach to treating patients with Her2 targeted therapy-resistant breast cancers.
• Mahmoud and co-workers reported the discovery of derivatives of pyrido[2,3-b]indole derivatives with 4-anilne and 6-substitutions as potent inhibitors of BRK and/or Her2 and described structure activity relationships (Mahmoud, K. A. Novel Inhibitors of Breast Cancer Relevant Kinases BRK and Her2. Med. Chem. Commun. 2014, 5:659-664). In a docking model developed by these researchers, the ATP-binding pocket in BRK was found to favor hydrophilic substituents. Mahmoud and co-workers further disclose a series of 4-anilinoa ⁇ -carbolines as novel Brk Inhibitors (Mahmoud, K. Z.
• inhibitors with single-digit nanomolar target engagement cell-based activity and an appealing overall DMPK profile, could be used as tool compounds to further validate Brk/PTK6 as a potential target for cancer treatment. None of these compounds have the chemical structure of formulas I, II, III, or IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-123, 200-139, or 200-149.
• Ren, P. et al. disclose a series of compounds and compositions as protein kinase inhibitors including BRK inhibitors (US 2010/0048552 A1).
• the novel compounds inhibit one or more protein kinases and are, therefore, expected to be useful in treatment of kinase-mediated diseases or conditions. None of these compounds have the chemical structure of formulas I, II, III, or IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-123, 200-139, or 200-149.
• compounds of formulas I, II, III, or IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-123, 200-139 or 200-149 including salts, prodrugs, and/or isomers thereof, can be used in preparation of medicaments for the treatment of a BRK-mediated disease or condition.
• the disease or condition is cancer.
• the types of cancers include breast, ovary and colon, and head and neck squamous cell carcinoma.
• the disease or condition is breast cancer including ERBB2/HER2-positive breast cancer and Her2 targeted therapy-resistant breast cancer.
• the amounts of compounds of formulas I, II, III, or IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-123, 200-139 or 200-149 to be administered can be determined by standard procedures taking into account factors such as the compounds IC 50 ; the biological half-life of the compound; the age, size, and weight of the subject; and the condition associated with the subject. In general, routine experimentation in clinical trials will determine specific ranges for optimal therapeutic effect for each therapeutic agent and each administrative protocol and administration to specific patients will be adjusted to within effective and safe ranges depending on the patient's condition and responsiveness to initial administration.
• doses of active compounds may range from about 0.01 mg/kg per day to, about 1000 mg/kg per day.
• Compounds described herein can be administered in single or multiple doses.
• the composition to be administered can include a plurality of different pharmacologically active compounds which can include a plurality of compounds of the invention including compounds of formulas I, II, III, and IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-123, 200-139 and 200-149.
• the invention provides methods for treating a BRK-mediated disease or condition in an animal or human subject, wherein the method involves administering to the subject an effective amount of a compound of formulas I, II, III, or IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-200-123, 200-139 or 200-149, in combination with one or more other therapies for treating the same disease or condition.
• Other therapies include medical procedures (such as surgeries), therapeutics, and/or radiation.
• Combination therapy can include administration of the compounds described herein with one or more other therapeutics at different times, or co-administration of the compounds described herein with one or more other therapeutics.
• dosages may be modified for one, or more of the compounds of the invention or other therapeutics used in combination, such modifications being a reduction in the dose amounts relative to a compound or therapy used alone.
• use in combination includes use with other medical procedures, therapeutics, and therapies where the other therapy or drug may be administered at different times, within a short time period, such as within 1, 2, 3, or 4-24 hours, or within a longer time period, such a 1-2 days, 2-4 days, 4-7 days, or 1-4 weeks.
• Use of the compounds of the invention can be in combination with a medical procedure such as surgery, performed on the subject once or infrequently, where the compounds are administered within a short time or longer time before or after the medical procedure.
• the methods and compounds will typically be used in therapy for human subjects with a kinase-mediated disease or condition. However, they may also be used to treat similar or identical indications in other animal subjects.
• the terms “subject,” “animal subject,” and the like refer to human and non-human vertebrates, i.e., mammals, such as non-human primates, sports and commercial animals, e.g., equines, bovines, porcines, ovines, rodents, and pets, e.g. canines and felines.
• the compounds of formulas I, II, III, or IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-200-123, 200-139 or 200-149 may be administered intravenously, intramuscularly, subcutaneously, orally, transdermally, transmucosal, rectally, or by inhalation.
• the dose may be administered as a bolus or infusion.
• compositions for oral use can be obtained, for example, by combining the compounds of formulas I, II, III, or IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-200-123, 200-139 or 200-149 with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
• Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP: povidone).
• disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate.
• the compounds of formulas I, II, III, or IV, 200-17, 200-73, 200-93, 200-93a, 200-93b, 200-115, 200-117, 200-200-123, 200-139 or 200-149 are formulated in sterile liquid solutions, preferably in physically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
• the compounds may be formulated in solid form and re-dissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
• administration of the compounds described herein can occur simultaneously or sequentially with chemotherapy or radiation. It is understood that administration of other therapeutics or drugs to treat a medical disease or condition can be by a different route of administration or by the same route of administration.
• the use in combination therapy for any route of administration includes delivery of compounds of the invention and one or more other drug therapeutics delivered by the same route of administration together in any formulation, or administered together, within an hour, 2 hours, 3 hours, up to 24 hours, in separate formulations or by different routes of administration.
• the invention also provides for a pharmaceutical combination, e.g., a kit, comprising (a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and (b) at least one co-agent.
• a pharmaceutical combination e.g., a kit, comprising (a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and (b) at least one co-agent.
• the kit can include instructions for its administration.
• the present invention also includes processes for the preparation of compounds of the invention.
• reactive functional groups for example hydroxy, amino, imino, thio, or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
• Conventional protecting groups can be used in accordance with standard practice, for example, see T. W. Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry,” John Wiley and Sons, 1991.
• Detailed examples for the synthesis of compounds 200-17, 200-73, 200-93 (resolution of isomers), 200-115, 200-117, 200-123, 200-139, and 200-149 can be found in the Examples.
• the intermediate (5) is reacted with 4-chlorobenzeneboronic acid and palladium dichloride to produce (3-amino-2,6-difluorophenyl)-[5-(4-chlorophenyl)-1-(2,6-dichlorobenzoyl)pyrrolo [2,3-b] pyridin-3-yl]methanone (6).
• the intermediate (6) is reacted with 3-(acetyloxy)-1-propanesulfonyl chloride to form N-[3-[5-(4-chlorophenyl)-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b] pyridine-3-carbonyl]-2,4-difluoro-phenyl] 3-(acetyloxy)propane-1-sulfonamide (7).
• the intermediate (7) is deprotected, removal of the dichlorobenzoyl group, using standard conditions to produce 200-17.
• the intermediate (36) is deprotected, removal of the dichlorobenzoyl group, using standard conditions to produce 200-93 as a mixture of (cis) and (trans) isomers.
• the two isomers are resolved by HPLC, and named 200-93a and 200-93b, respectively.
• the intermediate (200-111) is treated sodium borohydride to reduce the ketone to the alcohol and produce N-[3-[5-(4-chlorophenyl)-I-(2,6-dichlorobenzoyl)pyrrolo[2,3-b] pyridine-3-carbonyl]-2,4-difluoro-phenyl]-2-hydroxypropane-1-sulfonamide (200-113).
• the alcohol (200-113) is deprotected by removal of the dichlorobenzoyl group, using standard conditions to produce 200-115 consisting of a mixture of R and S isomers.
• Synthesis of 200-117 Compound 200-117 is synthesized using the method shown in Scheme 5 starting from N-[3-[5-(4-chlorophenyl)-1-(2,6-dichlorobenzoyl)pyrrolo[2,3-b] pyridine-3-carbonyl]-2,4-difluoro-phenyl]-2-oxopropane-1-sulfonamide (200-111). The protecting dichlorobenzoyl group is removed using standard conditions to produce 200-117.
• the mass spectrometry results indicated for a compound may have more than one value due to the isotope distribution of an atom in the molecule, such as a compound having a bromo or chloro substituent.
• Compound 200-117 was synthesized starting from N-[3-[5-(4-chlorophenyl)-I-(2,6-dichlorobenzoyl)pyrrolo[2,3-b] pyridine-3-carbonyl]-2,4-difluoro-phenyl]-2-oxopropane-1-sulfonamide (200-111) by the synthetic procedure shown in Scheme 5.
• Compound 200-149 was synthesized starting from N-[3-[5-(4-chlorophenyl)-I-(2,6-dichlorobenzoyl)pyrrolo[2,3-b] pyridine-3-carbonyl]-2,4-difluorophenyl]-2-methoxyethanesulfonamide (200-137) by the synthetic procedure shown in Scheme 8.
• MSA Off-chip Mobility Shift Assay
• T-47D (ATCC® HTB-133TM) was purchased from American Type Culture Collection (ATCC, Manassas, Va.). T-47D cells grew in DMDM medium (Gibco, Life Technologies) supplemented with 10% FBS (Gibco, Life Technologies) (complete medium) a T-75 flask at 37° C. under 5% CO 2 with saturated humidity.
• the culture medium was removed, the cell layer was rinsed with 10 mL Dulbecco's Phosphate-Buffered Saline (DPBS), and immediately following the treatment with 1 mL of 025% (w/v) Trypsin-EDTA solution at 37° C. for 5-15 min. A 9 mL aliquot of the complete medium was then gently dispersed over the surface of the cell layer for several times. The cell concentration was adjusted to 1 ⁇ 10 4 cells/mL with the complete medium. A 100 ⁇ L aliquot of the cell suspension was added to the well of a 96-well plate, and the plate was incubated overnight at 37° C. under 5% CO 2 with saturated humidity.
• DPBS Dulbecco's Phosphate-Buffered Saline
• the medium in each well was aspirated and replaced with a 100 ⁇ L aliquot of pre-warmed complete medium at 37° C. in the presence or absence of the test compounds at various concentrations from 0-100 ⁇ M.
• the test compounds were dissolved in DMSO, and the final DMSO concentration in the cell culture was no more than 1%.
• the plate was incubated for 72 hours at 37° C. under 5% CO 2 with saturated humidity.
• a 10 ⁇ L aliquot of PrestoBlue® Cell Viability reagent was added into the well, and the plate was incubated at 37° C. for 30 min.
• the absorption at 570 and 600 nm were measured with a SpectraMax Microplate reader (Molecular Devices).
• the absorbance at 570 nm was normalized to that at 600 nm.
• the normalized absorbance at 570 nm was used for IC 50 calculation following the median-effect plot method (T. C. Chou, Pharmacol Rev 2006, 58: 621-681).
• the IC 50 values for 200-17, 200-73, 200-93b, 200-115, 200-117, 200-123, 200-139 and 200-149 were less than 20 ⁇ M, while the IC 50 value for 200-93a was greater than 20 ⁇ M.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Epidemiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (1)

Applications Claiming Priority (4)

Related Parent Applications (1)

Related Child Applications (1)

Publications (2)

Family

ID=58518550

Family Applications (2)

Family Applications After (1)

Country Status (2)

Families Citing this family (11)

Citations (15)

• 2016
  • 2016-10-11 WO PCT/US2016/056439 patent/WO2017066193A1/fr active Application Filing
  • 2016-10-11 US US15/516,355 patent/US9890163B2/en active Active
• 2017
  • 2017-12-29 US US15/858,545 patent/US10106538B2/en not_active Expired - Fee Related

Patent Citations (18)

Non-Patent Citations (16)

Also Published As

Similar Documents

Legal Events